The present invention relates to a process for the preparation of maleate salt of 5-methoxy-1-[4xe2x80x2-(trifluoromethyl)phenyl]-1-pentanone O-(2-aminoethyl)oxime viz fluvoxamine maleate in a substantially pure form. Fluvoxamine maleate is an important drug used in the treatment of depression.
U.S. Pat. No. 4,085,225 discloses the process for the preparation of fluvoxamine maleate, a compound of formula I, by alkylation reaction of 5-methoxy-4xe2x80x2-trifluoromethylvalerophenone oxime, a compound of formula II, with 2-chloroethylamine hydrochloride in dimethylformamide in the presence of a base viz. potassium hydroxide for two days at 25xc2x0 C. 
Subsequently the solvent is removed under vacuum then the residue is acidified and extracted with ether to remove the unreacted oxime. The fluvoxamine base is then obtained by extraction into ether after basification, and the ether extract is washed with NaHCO3 solution. The fluvoxamine base is then treated with maleic acid in ethanol, and the residue obtained by concentration under vacuum is recrystallised from acetonitrile to obtain fluvoxamine maleate I. This process when attempted by us was found to be very time consuming. Moreover, the requirement of various solvents posed the problem of their recovery and re-usability.
In an alternate route described in the above mentioned patent, the oxime II is converted to I in a five step process viz., alkylation of II with ethylene oxide to give the hydroxyethyl compound III, which is converted to a mesylate derivative IV with methanesulfonyl chloride and triethylamine, and then aminated with ammonia to give fluvoxamine base. 
The base is then converted to the maleate salt I, which is finally purified by recrystallization from acetonitrile.
Although in principle, the process described gives the desired product, viz. fluvoxamine maleate I, it was not found to be attractive as it involves a number of unit operations, use of several solvents, and handling of toxic and explosive ethylene oxide, a potential carcinogen. The number of operations used result in long occupancy of reactors and utilities, and high-energy consumption making it a commercially unviable process on a large scale. Also, for large-scale operations, the use of several different solvents in the process poses ecological and other usual problems such as storage, their recovery and re-usability. Furthermore, purification of the intermediate III requires cumbersome technique viz. chromatography over silica gel.
The lengthy work-up procedure in U.S. Pat. No. 4,085,225 requires complete removal of organic solvents at different stages; a simple and efficient process has been found wherein:
(a) the alkylation reaction could occur very rapidly in a water immiscible inert aprotic solvent in the presence of a facilitator;
(b) the unwanted reaction components i.e. the excess base, salts and the added facilitator could be easily removed in one step by washing the reaction mixture with water;
(c) the organic layer containing fluvoxamine base treated with maleic acid; and
(d) the fluvoxamine maleate obtained in a substantially pure form by recrystallization.
It is thus an object of the present invention to provide a simple process for the preparation of fluvomaxine maleate I comprising of minimum number of unit operations and solvents, and the fluvoxamine maleate I produced is in a substantially pure form.
It is further object of the present invention to provide a process for the preparation of fluvomaxine maleate I by the use of a single water immiscible aprotic solvent in the presence of facilitator coupled with washing the reaction mixture with water such that the process requires very short reaction time and avoids an elaborate work-up procedure using several different solvents and a number of unit operations.
It is still further object of the present invention to provide a process for the preparation of fluvomaxine maleate I which essentially uses a single major aprotic organic solvent, which can be almost quantitatively recovered and re-used thus making the process cost-effective.
It is yet another object of the present invention to provide a process for the preparation of fluvomaxine maleate I in which a plurality of steps are carried out in a single reactor during commercial production to achieve efficiency and economy.
It is still further object of the present invention to provide a process for the preparation of fluvomaxine maleate I which conforms to British Pharmacopoeial specifications (British Pharmacopoeia, 1999, Vol I, British Pharmacopoeia Commission, HMSO Publication, London).
Thus the present invention relates to a simple and efficient process for the preparation of fluvoxamine maleate of formula I in a substantially pure form: 
The process comprising
a) reacting of oxime of formula II 
xe2x80x83with 2-chloroethylamine hydrochloride, in presence of a base and a facilitator in a water immiscible inert aprotic solvent;
b) washing the reaction mixture with water;
c) treating the organic layer containing fluvoxamine base with a solution of maleic acid in a protic solvent or water to obtain fluvoxamine maleate; and
d) recrystallising the fluvoxamine maleate thus obtained.
For the purpose of maleate salt formation in situ, due to the limitations of the solubility of maleic acid, its addition as a solution was studied in protic solvents and in water. In both the cases fluvoxamine maleate free from contaminants crystallized out, and could very easily be separated out by filtration, thus obviating many operations such as concentrations, extractions etc., and the use of several different solvents.
According to the process of the present invention, the oxime II is reacted with 2-chloroethylamine hydrochloride in the presence of a base. Examples of bases that may be used in the process of the present invention include an alkali metal alkoxide of C1 to C5 alcohols; an alkali metal hydroxide such as LiOH, NaOH, KOH, CsOH; and an alkali metal carbonate such as Li2CO3, Na2CO3, K2CO3, Cs2CO3. The bases that can preferably be employed are alkali metal hydroxides such as LiOH, NaOH, KOH, CsOH; most preferred being KOH. About 1 to 10 moles of base are used for one mole of oxime II. More preferably 4 to 5 moles of base are used for one mole of oxime II.
According to the process of the present invention, the oxime II is reacted with 2-chloroethylamine hydrochloride in the presence of a base in a water immiscible inert aprotic solvent. Examples of water immiscible inert aprotic solvents that may be used include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, aliphatic hydrocarbons with C5 to C10 carbons, which may be branched or linear, and aromatic hydrocarbon solvents such as benzene, toluene, or xylenes.
Preferably the solvent is selected from aromatic hydrocarbons such as toluene and xylenes. More preferably the solvent is toluene.
The rate of base mediated alkylation reaction of the oxime II, with 2-chloroethylamine hydrochloride to produce fluvoxamine base, in a water immiscible inert aprotic solvent, is enhanced in the presence of a facilitator such that substantially pure fluvoxamine maleate is easily prepared, in situ, by the addition of a solution of maleic acid in aprotic solvent, and subsequent recrystallization. The facilitator is selected from a substance that has the property to complex or solvate metal cations, for example, a polyether. Alternatively, the facilitator can be selected from substances that can exchange the metal cations with hydrophobic cations, for example, a quaternary ammonium salt or a quaternary ammonium hydroxide where substituents on the nitrogen are selected from alkyl or aralkyl groups, for example, benzyltrialkylammonium halide.
The polyether is preferably a cyclic polyether such as a crown ether or an acyclic polyether such as a poly(alkylene)glycol.
The poly(alkylene) glycol is preferably a poly(ethylene) glycol (PEG) and more preferably a poly(ethylene) glycol with an average molecular weight in the range between 200 to 10,000. Most preferably the poly(alkylene) glycol is a poly(ethylene) glycol (PEG) with an average molecular weight in the range between 200 to 1000.
The temperature at which the reaction between oxime II and 2-chloroethylamine hydrochloride is carried out ranges from 0xc2x0 C. to 140xc2x0 C., preferably between about 20xc2x0 C. to 60xc2x0 C. The selection of the temperature depends on the reaction mixture composition and particularly on the solvent and the facilitator used in the process.
In a preferred embodiment of the invention the process of the present invention is carried out in an aromatic hydrocarbon solvent in presence of alkali metal hydroxide as base, poly(ethylene) glycol with molecular weight 200 to 1000 as a facilitator at temperature between 20xc2x0 C. to 60xc2x0 C.
In a still preferred embodiment of the invention the process of the present invention is carried out in toluene in presence of KOH and poly(ethylene) glycol with molecular weight 400, at temperature between 30xc2x0 C. to 40xc2x0 C.
In a further preferred embodiment of the invention the process of the present invention is carried out in toluene in presence of KOH and poly(ethylene) glycol with molecular weight 400, at temperature between 30xc2x0 C. to 40xc2x0 C.; the mole ratio of KOH with respect to oxime is 4 to 5:1.
Upon completion of the reaction, water is added and the organic layer is separated. The organic layer containing fluvoxamine base is treated with a solution of maleic acid in water or a protic solvent, whereby the maleate salt of fluvoxamine crystallizes out.
Preferably solution of maleic acid in water or protic solvent selected from C1 to C5 alcohol like methanol or ethanol is used. Most preferably a solution of maleic acid in water is used.
The salt produced is purified by a simple step of recrystallization from a suitable solvent, preferably water, 2 to 6 volumes, preferably 3 volumes, to directly obtain substantially pure fluvoxamine maleate.
The principal advantage of the process of the present invention is that it is fast with a simple work-up procedure saving on time, solvents and energy consumption as a result. The process is cost-effective and suitable for scale-up on commercial basis.